Rhein, or 9,10-dihydro-4,5-dihydroxy-9,10-dioxo-2-anthracenecarboxylic acid, and diacerhein, its diacetylated derivative, that is to say 4,5-bis(acetyloxy)-9,10-dihydro-4,5-dihydroxy-9,10-dioxo-2-anthracenecarbo xylic acid, are described in numerous scientific publications as well as in patent FR-A-2,508,798. Diacerhein is well known as a medicament having antiarthritic activity, and is used in particular in the treatment of osteoarthritis. However, rhein and diacerhein have the disadvantage of being practically insoluble in water and in alcohols. Furthermore, diacerhein may be administered by the oral route, but it is not completely absorbed by the digestive tract, and this incomplete absorption could cause undesirable side effects, for example laxative effects. Moreover, the administration of rhein is thought to cause even more problems than that of diacerhein.
To overcome these difficulties, various derivatives as well as pharmaceutical compositions and specific galenic forms have been proposed in the literature. For example, patent EP-A-243,968 describes a water-soluble potassium salt of diacerhein which can be used in the preparation of compositions for parenteral administration.
It is known, moreover, that the solubilization and/or wettability of a substance can be improved by treatment by means of a surfactant, which generally has the effect of promoting bioavailability of the active ingredient. It is also known that the grinding of insoluble active ingredients in the presence of certain water-soluble polymers improves the solubility and bioavailability of the product (Yamamoto et al., J. Pharm. Sci. (1976) 65, p. 1484-88).
The grinding of the substances used in therapy can be carried out in ball or hammer mills of the customary type. The procedure can also be carried out by micronization in gaseous jet micronizers which have the advantage of not heating the substances to be micronized. The micronization technique has been used to develop a pharmaceutical composition based on bioavailable and orally administerable progesterone whose bioavailability is double that of the crystalline form previously known.
Patent EP-A-330,532 describes the comicronization of fenofibrate in the presence of sodium lauryl sulfate. On the other hand, M. Otsuda et al. (J.P.S. 84 (1995) p. 1434-37) have studied the micronization of phenitoin in the presence of a surfactant, and they have shown that the solubility of phenitoin is not improved in the case of comicronization with a surfactant such as sodium lauryl sulfate or a sucrose ester of stearic acid, whereas it is multiplied by 30 compared with the mixture of the powders, in the case of a cogrinding with sodium deoxycholate.
Moreover, even if the micronization or the grinding of a substance in the presence of a surfactant or of a sugar can increase its solubility, these parameters are not always adequate. For example, the bioavailability of micronized progesterone is not adequate and should be improved, for example by dispersion in carnauba wax. Such a technique is described in application WO-89,02742.
Thus, it appears that the properties of a substance treated by micronization or grinding, in particular its solubility and its bioavailability, are not predictable, it being possible to obtain contradictory results. Furthermore, an identical galenic formulation can provide good results with a substance and give the opposite result with another substance.